In each cell cycle, the sister chromatids produced by DMA replication must be divided equally between two daughter cells. The mitotic spindle generates the force to pull apart the sister chromatids, which attach to the spindle at the kinetochore, a multiprotein complex assembled on a specialized chromosomal domain known as the centromere. Once each kinetochore has achieved a stable and bioriented attachment to spindle microtubules from opposite poles chromosome segregation is permitted. However, improper microtubule-kinetochore interactions occur frequently and must be corrected. Defects that endanger chromosome segregation activate the spindle checkpoint, which halts the cell cycle and allows time to fix errors. While the mechanism of spindle checkpoint activation and maintenance is extensively studied, little is known about how defects are corrected to restore cell cycle progression. We hypothesize that spindle repair occurs in response to spindle damage, and propose the following three aims: (1) to characterize the process by which cells recover from spindle checkpoint arrest, (2) to perform a genetic screen in budding yeast to identify spindle repair genes, and (3) to characterize spindle repair gene products and functions. We will use budding yeast because of the ease of genetic and biochemical analyses, as well as the fact that each kinetochore has a single microtubule binding site which greatly simplifies these studies. First, we will learn how cells repair spindle damage. Spindle damage will be induced with the microtubule depolymerizing drug nocodazole, and then we will analyze the recovery from spindle checkpoint arrest by light microscopy when the drug is removed. Secondly, spindle repair genes will be identified in two complementary screens to isolate mutants that can mediate cell cycle arrest in the presence of a microtubule-depolymerizing drug, but cannot recover when the drug is removed because the damage was not repaired. Finally, spindle repair gene products will be characterized using biochemistry and proteomics. Taken together, these studies should identify pathways that mediate spindle repair and the mechanisms used to fix spindle damage. Ultimately, this work will explore a fundamental mechanism for cell division, as well as identify potential mechanisms underlying genomic stability that are perturbed in development and disease. All cancers and severe birth defects can be caused by cells with the wrong number of chromosomes. This can be the result of defects in the process that equally divides chromosomes between cells, chromosome segregation. We plan to identify and characterize how chromosome segregation errors are corrected, and ultimately devise ways to inhibit error correction in cancer cells in order to kill them.